Acute and chronic stress, a negative and permanent characteristic of present-day life, comprises the unfolding of three processes: first--the aggression of the body by stressors, in a continuous growth, diversification and perpetuation; second--the body response, which may be adaptively, maladaptively or pathologically stress-dependent; and third--the intense, accelerated and chronically accumulated wear and tear of the brain and of the organism, premature aging.
The adaptive response of the body (the general adaptation syndrome) consists of three successive stages: immediate adaptation, long-term adaptation and the stage of exhaustion--neuropsychic and biological impairment (SELYE, H., The evolution of the stress concept, American Scientist, 61, 692-699, 1973). Chronic wear and tear means the neuropsychic and biological progressive incapacitation; it results in the decrease of the adaptation capability and in the diminution of body vitality and resistance, and it is the consequence of accumulation in the course of time and stressful life events and stress-induced lesions. When the adaptation capabilities of the organism are exceeded, due to the intensification, frequency and chronicization of stress and impairment, diseases of adaptation appear, meaning the stress-dependent pathology: neuropsychiatric and psychosomatic illnesses (WILDER, J. F., PLUTCHIK, R., Stress and psychiatry (Cap. 25.11), pp. 1198-1203, In: KAPLAN, H. I., SADOCK, B. J. (Eds.), Comprehensive Textbook of Psychiatry/IV, vol. 1, Williams and Wilkins, Baltimore, 1985).
The human brain, through its triple functionality--neurobiological, psychic and social--and due to the loss, after birth, of the neuron regeneration capacity through cell division, represents the global "receiver" of stresses (ischemic, hypoxic, oxidative etc.) and the "storage" of chromic, progressive, neuropsychic and biological impairment. Thus, in the central nervous system, specific ultrastructural and biochimical imbalances and lesions are accumulated, reaching all levels of metabolism (energy, anabolism, catabolism), then they extend with age and determine the incapacitation of the brain and body functions. The cerebral blood flow diminution as a consequence of stress and aging (progressive chromic hypoxia) and the neuronal hypoanabolism (the disturbance and decrease of nucleic acid and protein synthesis, the reduction and impairment of Nissl bodies--crowds of rough endoplasmic reticulum and free ribosomes--and of Golgi apparatus) induce the diminution of plasticity and anabolic regeneration, both functional (enzymes and neurotransmitters) and ultrastructural (neurosomes and extensions), (TERRY, R. D., GERSHON, S. (Eds.), Aging, vol. 3 (Neurobiology of Aging), Raven Press, New York, 1976). Oxidative stress, neuronal hypercatabolism, lipid peroxidation, especially of membranes, and the premature chronic impairment of subcellular organelles, mainly mitochondria, in all cases finally result in a progressive accumulation of lipofuscin pigments (wear and tear pigments, age pigments, tertiary lysosomes, insoluble subcellular wastes coming from peroxidation, polymerization and cross-linkages by free radicals) in neurons and glial cells (RIGA, D., RIGA, S., POPESCU, A., CONSTANTINESCU, E., PERIETEANU, M., Subcellular genesis of the nerve lipofuscin pigments, 4th European Anatomical Congress, Basle, Switzerland, 1977; Acta Anatomica, 99, 307-308, 1977; ZS.-NAGY, I. (Ed.), Lipofuscin--1987: State of the Art, Academiai Kiado, Budapest, 1988).
The necessity to develop a specific drug having an etio-pathogenic action against stress, impairment and premature aging was determined by the profound negative consequences of stress:
a) at the individual level--professional failure, disease, premature aging and death, and PA1 b) at the level of the whole society--important economic and social losses, direct and indirect (COOPER, C., ARBOSE, J., Executive stress goes global, International Management, 39, 42-48, 1984). PA1 a) anxiolytics (minor tranquilizers): diazepam, meprobamate, methylpentynol, etifoxine; PA1 b) neuroleptics (major tranquilizers): chloropromazine, promethazine, azaperone; PA1 c) beta-adrenergic blockers: bunitrolol; PA1 d) antidepressants: tricyclic, tetracyclic compounds, alone or associated with neuroleptics; PA1 e) psychostimulants: caffeine, amphetamine or derivatives; PA1 f) sedatives and hypnotics: combining in the formula phenobarbital and codeine (Romanian Patents nos. 60376 and 64161). PA1 a) Some of these compositions contain polyvitamins: hydrosoluble (American Medical Association, AMA Drug Evaluations, Publishing Sciences Group, Acton, Mass., 1973), hydrosoluble together with liposoluble (U.S. Pat. No. 3,493,659), or polyvitamins with bioelements (French Patent no. 7404 M); PA1 b) Other mixtures associate amino acids with or without vitamins (acetylaspartic acid, arginine glutamate, citrulline with folic acid), or are based on aspartates (Romanian Patents nos. 55069 and 77472; French Patent no. 2521429), on glutamates (Romanian Patent no. 76141), or cysteine (Romanian Patent no. 74505), arginine (French Patent no. 2494113), or complex combinations usually built up, alongside with the above mentioned amino acids, from glycine, lysine, tyrosine, ornithine, histidine (French Patent no. 5937 M; Romanian Patent no. 76044); PA1 c) Other associations comprise stimulating substances and combinations thereof: amphetamine, amphetamine with caffeine, or caffeine with vitamins (Romanian Patents nos. 62137 and 66014). PA1 a) anti-oxidative and anti-catabolic stress compounds (anti-lipofuscinogenesis, lipofuscinolytics and for lipofuscin elimination): methionine plus aminoethanol phenoxyacetates and/or aminoethyl phenoxyacetamides); PA1 b) anti-anabolic stress components (for functional and ultrastructural anabolic regeneration): hydrooxopyrimidine carboxylates and/or oxopyrrolidine acetamides with potassium, zinc and lithium; PA1 c) vasodilators (anti-hypoxic and anti-ischemic stress) and normolipidemic compounds: nicotinic alcohol and/or acid or derivatives thereof with magnesium and iodine; PA1 d) energo-active and e) anti-toxic components: aspartate, fructose, vitamin B.sub.1, vitamin B.sub.6, monoacid phosphate and sulfate. PA1 a) for controlled delivery in the release and absorption of the active compounds from the drug, the pharmaceutical preparation of the composition in two complementary types of capsules or film-coated tablets (gastrosoluble and enterosoluble units), the latter being enteric-coated, and PA1 b) for achieving the prolonged anti-ischemic and anti-hypoxic actions, the nicotinic alcohol or acid, or its derivatives from the composition of the enterosoluble capsule or film-coated tablet is retarded, under the form of granule or tablet. PA1 it represents a new drug and a new pharmacotherapeutical strategy in the fields of health promotion and in the prophylaxis, control and treatment of stress, biological wear and tear, premature aging, stress-related illnesses; PA1 it was elaborated and tested according to the biological drug conception, carrying out a synergistic biological, neurometabolic and cell-trophic (cerebral, hepatic, myocardial and general) composition, resulting in a multiple therapeutic efficacy, without toxicity and adverse reactions, without tolerance and dependence; PA1 it was created and checked up in a specific therapeutic conception, namely etio-pathogenic and homeostatic, against stress, impairment and aging, thus ensuring higher therapeutic efficiency, based on its active constituents (anti-oxidative and anti-catabolic stress, anti-anabolic stress, vasodilative--anti-hypoxic and anti-ischemic stress--and normolipidemic, energo-active and anti-toxic compounds), in free radical pathology, hypercatabolic and hypoanabolic states, in hypoxic-ischemic pathology, in dyslipidemias, in energetic exhaustion and toxic-deficient pathology; PA1 its biological composition and its specific anti-stress action determine a larege area of prophylactic, therapeutic and recovering uses, for the whole scale of ages (child, young man, adult, old man), for both healthy and sick persons; PA1 it is meant for healthy people, especially during activities with a high stressant and performing coefficient, because it antagonizes the anti-homeostatic action of stress and impairment (at neuropsychic and biological levels) and enhances the working power in overstressing conditions through increasing the resistance to psychic (intellectual) and physical (biological) effort; PA1 it is meant for patients in stress-dependent, psychosomatic, psychiatric and neurologic pathology, in geriatrics and internal medicine. PA1 in case of oral administration, it allows maximum bioavailability and therapeutic efficiency; PA1 it ensures controlled guidance in the release and absorption of active substances from the drug, by formulating the composition in two complementary types of pharmaceutical units (capsules or film-coated tablets): gastrosoluble and enterosoluble; PA1 for the enteric coating of the enterosoluble unit, it employs a technologic procedure completely non-toxic and non-polluting, namely the spraying with aqueous dispersion of gastroresistant-enterosoluble polymer; PA1 it ensures a prolonged or sustained anti-ischemic and anti-hypoxic action by timed-release of the vasodilative component from the enterosoluble unit; PA1 the different colouring of the two complementary units, gastro- and enterosoluble, and the drug package in the form of calendar-blister, in usual conditions under silica gel protection or under vacuum package technology, ensures correctness, easiness, differentiation and evidence (daily, weekly, monthly) of the treatment and the suitable preservability of the drug; PA1 thanks to its dosage flexibility, it makes possible the differentiation of anti-stress and anti-impairment treatment depending on individual features and neuropsychic reactivity, as well as on obtaining at brain level mainly the anti-oxidative and anti-catabolic stress or anti-anabolic stress action; PA1 it offers the possibility to administer the drug by chronotherapeutic criteria (chronobiological posology).
From the prior art it can be seen that efforts made for the production of drugs efficient in the control and treatment of stress and impairment have so far failed to produce a specific drug with an etio-pathogenic action; only symptomatological purposes or energizing effects have been fulfilled.
Thus, for improving the symptomatology induced by stress, dysadaptation, maladaptation responses to stress and the stress-related disorders (anxiety, depression, asthenia, sleeplessness, neurotic, neurovegetative and psychosomatic disorders) the use of psychotropic medication is known (POLDINGER, W., SCHMIDLIN, P. E., WIDER, F., Index Psychopharmacorum, H. Huber, Bern, 1983). Depending on the prevailing symptomatology, the following are known as having been used:
These psychotropic drugs have the disadvantage of representing only a predominant symptomatic medication, without an etio-pathogenic action against stress; they do not reduce chronic impairment caused by stress, they do not act against stress through anabolic regeneration, they modify the normal (anti-stress) reactions of body adaptation and bring about numerous adverse reactions. Furthermore, the anxiolytic and psychostimulant drugs (of the amphetamine and caffeine type) often call for increasing posology, due to phenomena of acquired tolerance and determine, as important adverse reactions, the dependence on psychoactive substances (LADER, M., Benzodiazepines--the opium of the masses?, pp. 609-615, In: SMITH, A. D., LLINAS, R., KOSTYUK, P. G. (Eds.), Commentaries in the Neurosciences, Pergamon Press, Oxford, 1980; W.H.O. Europe, Prevention of Mental Psychosocial and Neurological Disorders in the European Region, 38th Session, Copenhagen, 12-17 September, 1988).
One also knows many anti-stress drug compositions used for energizing, activatory, stimulating, trophic, tonic, fortifying--neuropsychic and/or biological--purposes. They are employed in treating disorders caused by acute and chronic stress, by stress-dependent pathology and especially against their most frequent consequences: nervous, psychic and biological exhaustion, accelerated chronic impairment, premature senescence.
These products, even when they are complex drug associations, have the drawback of not achieving an etio-pathogenic anti-stress therapy by simultaneous coupling of some multiple (vasodilative, normolipidemic, energo-active, anti-toxic, of catabolic regulation--lipofuscinolysis and anabolic regeneration) actions; they are not preclinically tested in antagonization of the experimental stress induced in animals, they cannot prevent or decelerate nervous wear and tear by antagonization of the oxidative stress and do not support the natural adaptation mechanisms--anti-stress mechanisms. Furthermore, especially drugs that associate methylxanthines and/or amphetamines are disadvantageous, because they form an incomplete, limited medication, of short-term effects, which in case of chronic administration, or in large doses, determine other new imbalances, contributing to the enhancement of those pre-existent, to the diminution of neuropsychic and biological resistance to stress, intensifying cellular catabolism and maladaptive reactions against stress; moreover, their use induces many adverse reactions (SYED, I. B., The effects of caffeine, Journal of the American Pharmaceutical Association, NS 16, 568-572, 1976; IVERSEN, L. L., IVERSEN, S. D., SNYDER, S. H. (Eds.), Handbook of Psychopharmacology, vol. 11 (Stimulants), Plenum Press, New York, 1978).
The use of methionine in hepatic pathology, as a hepatoprotective compound is well known (WADE, A., REYNOLDS, J. E. F. (Eds.), The Extra Pharmacopoeia, The Pharmaceutical Press, London, 1978). We found out by successive investigations that methionine additionally has a specific neurotropic action and interferes etio-pathogenically against stress. In this way we demonstrated the antagonization effect of chronic oxidative stress, determined by the diminution of lipofuscin pigments in the brain (telencephalon and diencephalon) of old rats, using quantitative histochemical methods (RIGA, S., PAMBUCCIAN, G., OERIU, S., Changes in lipofuscin pigments of rat central nervous system under --SH groups' releasing substances' influence, 9th International Congress of Gerontology, vol. 3 (Section Session, Abstracts), abstract no. 1103, p. 383, Kiev, U.S.S.R., 1972). Subsequently, we emphasized its complex action anti-stress, anti-impairment and anti-aging (catabolic regulation--anti-lipofuscinogenesis, lipofuscinolysis, and anabolic regeneration--the increase of RNA synthesis) at the nervous system level of old rats, using a complex methodology: selective isolations of living nerve cells from brain, morphometrical and biochemical methods (RIGA, S., Studies on Nucleic Acids in the Central Nervous System in Senescence Processes, Ph. D. Thesis, Institute of Medicine and Pharmacy, Bucharest, 1976, in Romanian).
It is also known that meclofenoxate, thanks to its actions of energetic and metabolic regulation on nerve cells, has a wide-spread area of clinical use in psychiatry, neurology as well as in the pathology determined by the hypoxic stress aggression of the brain--geriatrics, neurosurgery, anesthesiology, intensive care (COIRAULT, R., DELIGNE, P., ROUIF, J., Une orientation therapeutique nouvelle. L'A.N.P. 235 (ester dimethyl-amino-ethylique de l'acide para-chloro-phenoxy-acetique), Agressologie, 1, 113-138, 1960, in French). Afterwards, using light microscopy-histochemistry (qualitative only), the property of meclofenoxate to decrease lipofuscin pigments in the nervous system of old guinea pigs was emphasized (NANDY, K., BOURNE, G. H., Effect of centrophenoxine on the lipofuscin pigments in the neurons of senile guinea-pigs, Nature (Lond.), 210, 313-314, 1966); it was also demonstrated by electron microscopy (HASAN, M., GLEES, P., EL-GHAZZAWI, E., Age-associated changes in the hypothalamus of the guinea pig: effect of dimethylaminoethyl p-chlorophenoxyacetate. An electron microscopic and histochemical study, Experimental Gerontology, 9, 153-159, 1974). Our researches, having priority as preclinical methodology (quantitative--morphometry and qualitative--type of distribution, autofluorescence, histochemistry) and our trivalent experimental pattern (statistical comparison of three groups--control young, control old and treated old) have demonstrated the meclofenoxate action of specific and intense decrease of lipofuscin pigments in the brain of old rats; based on that, the authors of the present invention introduced in the scientific literature in the art the concept of lipofuscinolysis (RIGA, S., RIGA, D., Effects of centrophenoxine on the lipofuscin pigments in the nervous system of old rats, Brain Research, 72, 265-275, 1974), sustaining it also by electron microscopy (RIGA, D., RIGA, S., Selektive lipofuszinolytische Effekte von Centrophenoxin am Nervensystem alter Ratten, pp. 22-27, In: KUGLER, J. (Ed.), Himstoffwechsel und Himdurchblutung, Schnetztor Verlag, Konstanz, Schweiz, 1977). Later on this concept was used by other authors too. As a result of its lipofuscinolytic action, proof of the antagonization of oxidative stress, meclofenoxate acts etio-pathogenically against brain stress, impairment and aging (RIGA, S., RIGA, D., Dynamics of lipofuscin pigments, directing factor of brain aging, 6e Congres Medical International de la Federation Internationale des Resistants, (F.I.R.), Prague, Tchecoslovaquie, le 30 novembre--3 decembre 1976, Resumes, p. 70, 1976) and in deceleration of aging rate (ZS.-NAGY, I., An attempt to answer the questions of theoretical gerontology on the basis of the membrane hypothesis of aging, Advances in the Biosciences, 64, 393-413, 1987).
The two above mentioned substances, administered separately or without an anti-stress potentiation by means of a neurometabolic composition with an etio-pathogenic action, are disadvantageous because they offer only an incomplete protection of the brain against stress, impairment and aging, while their actions of functional and metabolic regulation, as well as of subcellular regeneration are only partial.